BMS 200 Diabetes Pathogenesis Part 2

Twin Cycle Hypothesis and Type 2 Diabetes Mellitus (T2DM)

• T2DM involves a transition from insulin resistance to the loss of beta cell mass due to dysregulated lipid and glucose metabolism across multiple organs.
• Early insulin resistance initiated by excess caloric intake and impaired nutrient clearance by skeletal muscle triggers the twin cycle hypothesis.

First Cycle - The Liver

• Diabetic patients reach a “tipping point” when normal energy storage becomes saturated.
• Energy should ideally be stored in subcutaneous fat, muscle, liver, and some in visceral fat; insulin receptors must be sensitive for effective storage.
• Positive energy balance leads to skeletal muscle and subcutaneous fat insulin resistance, resulting in prolonged elevated glucose and free fatty acids (FFAs) in circulation.
• Elevated FFAs cause the liver to respond by either burning energy (beta oxidation), storing it (hepatic steatosis), or exporting it (VLDL production).
• Insulin resistance creates an imbalance between glucagon and insulin in liver physiology, causing lipid accumulation, increased gluconeogenesis, and enhanced VLDL export.

Consequences of Insulin Resistance in Liver

• Increased liver fat leads to inappropriate gluconeogenesis and heightened blood glucose levels, further straining pancreatic insulin secretion.
• Elevated circulating FFAs, especially palmitic acid, activate Toll-like receptors (TLRs) exacerbating insulin resistance in hepatocytes.

Second Cycle - The Pancreas

• Pancreas changes in T2DM, including intrapancreatic fat accumulation, have become better characterized; fatty infiltration around acinar cells is common.
• The liver delivers excess triglycerides (TGs) to the pancreas, correlated with fibrosis and fat accumulation, particularly affecting pancreatic beta-cells.
• Fatty pancreas may lead to apoptosis or dedifferentiation of beta-cells; excess fat and glucose may alter beta-cell function, mimicking alpha-cell behavior.

Positive Feedback Loop in T2DM

• Insulin resistance increases hepatic steatosis and VLDL output, causing triglyceride and FFA accumulation in the pancreas, compromising insulin secretion.
• Resulting hyperglycemia promotes fat conversion and further increases circulating FFAs, worsening the diabetic state.

Endogenous Lipid Pathway Insights

• VLDL, primarily formed by the liver, consists of triglycerides, phospholipids, cholesteryl esters, and proteins (ApoC-II, ApoA-V) for peripheral lipoprotein lipase (LPL) activity.
• IDL is generated as VLDL loses triglycerides and is cleared largely by the liver via ApoE receptors on hepatocytes.
• LDL, being primarily cholesterol-rich, is also cleared by the liver and can oxidize if not cleared, escalating atherosclerosis risk.

Adipose Tissue Saturation

• Subcutaneous fat has a capacity limit for triglyceride storage influenced by genetics, age, and sex.
• In insulin resistance, adipocytes are less effective at storing triglycerides, releasing FFAs instead.
• Adiponectin secretion by subcutaneous fat doesn’t keep pace with leptin from both fat types, leading to higher leptin/adiponectin ratios and poor regulation of food intake.

Evidence and Challenges

• The twin cycle hypothesis is comprehensive and complex, presenting challenges in proving due to its detailed nature and the various interactions involved.

The Liver's Response to Elevated FFAs

• The liver handles elevated free fatty acids (FFAs) through three pathways: beta oxidation for energy, storage as hepatic steatosis, or exporting via Very Low-Density Lipoprotein (VLDL) production.
• Hepatic steatosis, or fat accumulation, is an undesirable condition linked to metabolic disorders.
• VLDL characteristics include being rich in triglycerides and containing apoproteins like ApoB-100, ApoA-V, and ApoC-II for lipid transport and metabolism.

Insulin Resistance and Liver Function

• Insulin resistance involves disrupted glucagon and insulin signaling rather than merely inhibiting insulin.
• Long-term insulin resistance, such as in Type 2 Diabetes Mellitus (T2DM), leads to lipid accumulation in the liver, worsened gluconeogenesis, and hyperglycemia.
• Elevated circulating FFAs from insulin-resistant adipocytes are taken up by hepatocytes, leading to increased triglyceride production and VLDL export, compounding metabolic issues.

The Twin Cycle Hypothesis

• The pancreas plays a critical role in T2DM progression, characterized by intrapancreatic fat accumulation affecting insulin secretion.
• Initial hypotheses suggested that increased fat within the pancreas leads to apoptosis of beta-cells, but newer studies also consider beta-cell de-differentiation as a potential factor.
• Improvements in T2DM have been linked to decreases in pancreatic fat and liver steatosis.

Feedback Loop in Metabolic Dysfunction

• A negative feedback loop exists: insulin resistance causes hepatic steatosis and heightened VLDL output, leading to fat buildup in the pancreas, impaired insulin secretion, and worsening hyperglycemia.
• Lipotoxicity from elevated FFAs exacerbates insulin resistance and overall metabolic dysfunction.

Endogenous Lipoprotein Pathway

• VLDL, synthesized in the liver, predominantly contains triglycerides and apoproteins (ApoC-II, ApoA-V, and ApoB-100) essential for triglyceride metabolism.
• As VLDL loses triglycerides, it forms Intermediate-Density Lipoprotein (IDL) and eventually Low-Density Lipoprotein (LDL), which is cleared by liver receptors.
• Accumulation of non-cleared LDL can lead to oxidation, increasing atherosclerosis risk.

Subcutaneous Fat and Insulin Resistance

• Adipose tissue has a limit on fat storage, affected by genetic and demographic factors.
• Insulin resistance diminishes the ability of adipocytes to store triglycerides, increasing FFAs in circulation.
• The balance of adipokines secreted by fat tissue (leptin and adiponectin) becomes disrupted in T2DM, worsening appetite regulation and insulin sensitivity.

DiRECT Trial Findings

• The DiRECT trial involved 306 T2DM participants undergoing a structured weight-loss program, highlighting significant metabolic improvements.
• Participants in the intervention group lost an average of 15 kg or more within 12 months, emphasizing the potential for weight loss in reversing T2DM effects and improving health outcomes.